Diabetic retinopathy is caused by chronic exposure of the retinal tissue to glucose owing to uncontrolled or poorly controlled diabetes. It is a leading cause of sight-threatening blindness among adults with diabetes, with significant morbidity among those who need to manage early stages of this disease. It has lifelong consequences for those living with diabetes, and the financial burden of its treatment is immense. We propose to capitalize on the endogamous structure of the population in Chennai, India, to map common and rare susceptibility loci. We will leverage the existing infrastructure for standardized data collection, with multifaceted phenotyping of diabetic retinopathy, established by the SN DREAMS project at the Vision Research Center, in Sankara Nethralaya. Focusing on proliferative disease, and diabetic macular edema, we will examine genetic variation in retinopathy cases and diabetic controls without retinopathy using the cosmopolitan MEG array, and S. Indian-specific imputation of markers using a variety of public and private data. We propose to conduct extensive modeling of covariates, such as HbA1C, and lipid levels, in an effort to account for the architecture of the exposures. We will also target consanguineous families for whole genome sequencing in order to find genes for diabetic retinopathy, utilizing identity-by-descent sharing and the endogamous population structure with its unique haplotype structures. This project will enable us to better define the genetic architecture of diabetic retinopathy in India, and worldwide.